Endogenous sex hormone levels and breast cancer risk

Sex-steroid hormones are a major determinant of the risk of breast cancer. We evaluated the relationship between obesity and endogenous estrogen levels in 79 healthy, postmenopausal women. Thirty-nine of the women were siblings of patients with postmenopausal-onset breast cancer; the remaining women were age-matched (+/- 10 yr) controls. Our hypothesis was that the siblings of the breast cancer patients would weigh more and that this excess weight would lead to higher serum estrone levels. The choice of unaffected family members of breast cancer patients reduces the concern that results may have been influenced by the cancer rather than antecedent to its development. Our findings demonstrated a statistically significant excess estrone level in the siblings compared to the controls (58.9 vs 47.8 pg/ml, P = 0.005). The siblings weighed 4.3 kg more than the controls. Matched pairs analysis (sibling-control), adjusting for weight, also showed significant differences in serum estrone levels. These differences were observed despite comparability in dietary intake, medication use, and personal medical history. These findings represent the first time that higher estrogen levels have been measured in siblings of postmenopausal breast cancer patients. This observation may represent an important link in our understanding of the relationship between genetic and environmental risk factors of breast cancer. One approach to subsequent genetic studies of breast cancer may be to focus on the possible biological determinants such as sex-steroid hormone level receptors, oncogenes, and gene products and not on the "familial aggregation" of breast cancer.     

Sex differences in the subjective and reinforcing effects of cigarette nicotine dose

RATIONALE: Some research with novel nicotine delivery methods suggests that nicotine itself may be less reinforcing in women than in men. However, sex differences in the reinforcing effects of nicotine dose via cigarette smoking have received little attention. OBJECTIVES: Sex differences in the subjective and reinforcing effects of smoking were examined as a function of two cigarette nicotine "dose" levels (moderate - subjects' preferred brand, > or = 0.7 mg yield; low - Carlton "ultra-light", 0.1 mg yield). METHODS: Male and female smokers ( n = 30) participated in three sessions, the first two involving independent assessment (only one brand available), and the third involving concurrent assessment (both brands available), of subjective ratings (e.g. "liking") and reinforcement for the two cigarette brands. Subjects were blind to the brand of each cigarette, and subjects abstained overnight prior to each session. Reinforcement was determined by responses on a computer task to earn single puffs on the designated cigarette. RESULTS: Subjective ratings differed between the low versus moderate cigarette nicotine dose under both independent and concurrent assessment conditions, as expected. Notably, this dose difference was smaller in women than in men (i.e. significant sex by dose interactions). The dose effect on smoke reinforcement also was smaller in women than men, but only under the independent and not concurrent assessment condition. CONCLUSIONS: These results indicate that cigarette nicotine dose is a less important influence on the subjective and, under some conditions, reinforcing effects of smoking in women than in men.     

Environmental stimuli promote the acquisition of nicotine self-administration in rats

RATIONALE: Environmental stimuli associated with drugs of abuse are believed to play a major role in the motivation to take drugs, drug dependence, and relapse. Previous work from this laboratory demonstrated that the response-contingent presentation of drug-related, visual cues was at least as important as nicotine in the maintenance, extinction and reacquisition of self-administration in experienced rats. OBJECTIVES: In the present research, we asked whether these same visual cues are effective in promoting the acquisition of operant responding in drug naive rats. METHODS: Male Sprague-Dawley rats were tested for self-administration of IV nicotine (0.03 mg/kg, free base) in 1-h daily sessions when infusions were or were not paired with two lighting events: a 1-s cue light, followed by a 1-min period during which the chamber light was turned off and responding was not reinforced. RESULTS: Rats tested with cues plus nicotine rapidly acquired self-administration and increased their lever pressing rates as the schedule progressed from FR1 to FR5. Without cues, the rate of nicotine self-administration was low and no adjustments were made in response to increasing schedule demands. While one of the stimuli, turning off the chamber light, was shown to have primary reinforcing properties, its association with nicotine produced a synergistic enhancement of lever pressing. Acquisition of operant responding was also enhanced, but to a lesser extent, by a previously neutral compound stimulus, i.e. the nicotine-paired cue light presented with a 1-s tone. CONCLUSIONS: These results illustrate a powerful interaction between environmental stimuli and nicotine in the acquisition of operant responding and indicate that both intrinsically reinforcing and previously neutral cues can participate in this effect.     

Long-term oscillation of corticosterone following intermittent cocaine

Summary. We have shown that repeated administration of cocaine, as well as other drugs and nondrug stressors, can induce alternating increases and decreases in several neurotransmitter and endocrine endpoints, which we call oscillation. Oscillation studies have typically used 3–4 pretreatments with cocaine or other agents, raising the question of whether oscillation lasts beyond this point. Using plasma corticosterone as our endpoint measure, we therefore inquired whether oscillation would persist across eight administrations of cocaine over a 28-day period. We report oscillation of corticosterone levels persisting across all eight cocaine groups. Our data also indicate that the degree of oscillation increases with the intertreatment interval. Received May 4, 1999; accepted August 24, 1999     

Preoptic knife cuts and sexual behavior in male rats

Knife cuts aimed at severing either the medial-lateral or dorsal fiber connections of the medial preoptic-anterior hypothalamus (MPOAH) produced two clearly distinguishable patterns of copulatory deficits in male rats. On the other hand, transverse cuts, which were designed to destroy longitudinal connections on either the anterior or posterior end of the MPOAH, did not affect sexual behavior. Males with sagittal cuts exhibited deficits primarily in the initiation of copulation. In contrast, those with dorsal cuts showed alterations primarily in the execution of copulatory behavior. Combined behavioral and anatomical evidence was interpreted as suggesting that the MOPAH has at least two regulatory functions related to sex behavior: (1) it is involved in the mediation of the initiation of copulation through its lateral connections with the medial forebrain bundle, and (2) it influences the achievement of ejaculation and the subsequent refractory period through its dorsal connections with the amygdala and the hippocampus.     

Ventral midbrain involvement in copulatory behavior of the male rat

Stimulation bound copulation was obtained from a ventral midbrain extension of the hypothalamic medial forebrain bundle. Electrical stimulation at this site accelerated the achievement of ejaculation and the resumption of copulation after ejaculation. Sexual activity was temporarily depressed immediately after stimulation. The results are discussed in terms of a preoptic medial forebrain bundle ventral midbrain system influencing copulation in the male rat.     

Substantia nigra dopamine neurons: Alterations in basal discharge rates and autoreceptor sensitivity induced by estrogen

Treatment with estrogen was shown to exert differential effects on two subpopulations of putative substantia nigra dopamine-containing neurons as demonstrated by single cell electrophysiological techniques. The acute administration of 17β-estradiol to anesthetized, ovariectomized female rats increased the spontaneous activity of Type A, but decreased that of Type B neurons in a dose-dependent manner. Moreover, pretreatment with 17β-estradiol benzoate, 48 hr before recording, increased the response of Type A neurons to both small doses of the dopamine receptor agonist, apomorphine, and to microiontophoretically applied dopamine. In contrast, the responsiveness of Type B neurons to these same manipulations was significantly diminished by this pretreatment. Taken together, these data suggest that prior exposure to estrogen enhances the sensitivity of dopamine autoreceptors located on Type A neurons while attenuating the sensitivity of the autoreceptors located on Type B cells. The demonstration that estrogen has complex, bidirectional, rather than simple, unidirectional influences on the activity of dopamine cells of the nigra might aid in the understanding of current controversies in both the experimental animal and human clinical literature bearing on behaviorally relevant interactions between estrogen and brain dopamine systems.     

The influence of instructions and nicotine dose on the subjective and reinforcing effects of smoking

Subjective and reinforcing effects of smoking a cigarette were examined within a 2 x 2 modified balanced-placebo design, which manipulated instructions about nicotine content (i.e., told regular nicotine vs. told low nicotine) and actual nicotine dose (given a regular nicotine brand vs. a denicotinized brand). Most ratings of the nicotine content and reward value of cigarettes were higher for those told regular nicotine versus told low nicotine, and for those given regular nicotine versus given low nicotine. Nicotine and instructions did not affect craving, withdrawal, or smoke-reinforced responding, but instructions affected the number of puffs earned for those given low nicotine (i.e., placebo effect). Thus, verbal information (instructions) can influence some responses to smoking consistent with the presence of placebo and antiplacebo effects.     

Importance of nonpharmacological factors in nicotine self-administration

There is mounting evidence that nonpharmacological factors critically modulate the effects of several drugs of abuse both in humans and experimental animals. This paper reviews research from this laboratory on one factor that influences the degree to which nicotine is self-administered: environmental stimuli that form the context within which nicotine is taken. The results suggest that the direct, pharmacological actions of nicotine are necessary but not sufficient to explain either the high rates of self-administration exhibited by laboratory animals or cigarette smoking by humans, and that future investigations on the neurophysiological effects of nicotine that underlie smoking behavior must take into account the environmental context within which the behavior occurs.